The importance of touch is undeniable: it is an essential sense for our survival that allows us to navigate the physical world. It is vital not onl for simple daily activities such as feeding and dressing, but also for more complicated social interactions such as mating, bonding and successful child rearing. Despite decades of research, the molecular and cellular mechanisms underlying touch sensitivity are largely unknown. The long- term goal of this research is to elucidate mechanisms of touch reception using the Merkel cell-neurite complex as a model for mechanosensory signaling in mammals. The objective of this application is to test whether Merkel-cell synaptic activity is involved in generation of SAI responses. Merkel cells together with cutaneous sensory afferents form gentle-touch receptors, which generate slowly adapting type I (SAI) responses. SAI responses are thought to mediate high tactile acuity in mammals that rely on discriminative touch to recognize and manipulate objects. It has long been proposed that Merkel cells are mechanosensory cells that transduce sensory information to cutaneous afferents via excitatory neurotransmission. Alternatively, Merkel cells might be accessory cells that modulate sensory output of mechanosensitive SAI afferents via neurotransmission. Ultrastructural and molecular studies suggest that Merkel cells synapse with SAI afferents. A plethora of potential neurotransmitters have been associated with Merkel cells, including glutamate, serotonin, ATP, met-enkephalin and others. However, functional studies have yielded contradictory results regarding the involvement of these neurotransmitters. Moreover, a direct demonstration that Merkel cells have functional synapses is still lacking after more than a century of investigation. This application's central hypothesisis that Merkel cells release excitatory neurotransmitters to elicit action potentials in SAI afferents Aim 1 will test whether synaptic vesicle release from Merkel cells is necessary for touch-evoked SAI responses. I will record SAI afferent's activity in mice whose Merkel cells express tetanus neurotoxin light chain (TeNT), an inhibitor of synaptic vesicle release. Aim 2 will test whether Merkel-cell synaptic activity is sufficient to elicit action potentials in SAI afferents and, if so will identify underlying excitatory neurotransmitters. Since Merkel cells and SAI afferents are tightly juxtaposed in the skin, touch stimuli cannot be used to independently activate each cell type in situ. To break this barrier, in Aim 2 I use selective expression of the light-gated ion channel channelrhodopsin-2 (ChR2) in Merkel cells. This allows me to test if selective excitation of Merkel cells with light evokes action potentials in SAI afferents.